Ignite Creation Date:
2024-05-05 @ 11:46 AM
Last Modification Date:
2024-10-26 @ 9:13 AM
Study NCT ID:
NCT00127998
Status:
COMPLETED
Last Update Posted:
2006-08-16
First Post:
2005-07-07
Brief Title:
Antimalarial Drug Resistance in Mali
Sponsor:
Centers for Disease Control and Prevention
Organization:
Centers for Disease Control and Prevention
Study Overview
Official Title:
Characterization of Novel Molecular Tools for the Epidemiological Surveillance of Antimalarial Drug Resistance in Mali
Status:
COMPLETED
Status Verified Date:
2006-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Resistance of Plasmodium falciparum malaria to current antimalarial drugs and the continuing development of resistance to new antimalarial formulations is one of the major obstacles to effective malaria control and case management Efficient comprehensive and validated methods for monitoring drug resistance in advance of the development of resistance to the antimalarial drugs that are in use are urgently needed Molecular markers of genetic polymorphisms that give rise to resistant P falciparum parasites and methods in population genetics for evaluating the data can be valuable tools for monitoring drug resistance in the field This study aims to
1 Prospectively measure the in vivo response of P falciparum malaria in Mali to several different antimalarial drugs and drug combinations chloroquine CQ sulfadoxine-pyrimethamine SP amodiaquine AQ sulfadoxine-pyrimethamine in combination with amodiaquine SPAQ amodiaquine in combination with artesunate AQAS sulfadoxine-pyrimethamine in combination with artesunate SPAS and artemether-lumefantrine Co-artem In one site with preliminary data showing a high rate of P falciparum resistance to mefloquine MQ this drug will also be tested
2 Measure the frequencies of molecular markers for antimalarial drug resistance and examine how those results relate to the efficacy of these drugs in treating clinical malaria
3 Measure drug levels at 3 days and correlate with efficacy results
4 Examine early clinical parasitologic and clinical predictors of late treatment failure
5 Use the knowledge gained in Aims 1-3 to develop a molecular tool for a countrywide resistance surveillance system for antimalarial drugs
1 Prospectively measure the in vivo response of P falciparum malaria in Mali to several different antimalarial drugs and drug combinations chloroquine CQ sulfadoxine-pyrimethamine SP amodiaquine AQ sulfadoxine-pyrimethamine in combination with amodiaquine SPAQ amodiaquine in combination with artesunate AQAS sulfadoxine-pyrimethamine in combination with artesunate SPAS and artemether-lumefantrine Co-artem In one site with preliminary data showing a high rate of P falciparum resistance to mefloquine MQ this drug will also be tested
2 Measure the frequencies of molecular markers for antimalarial drug resistance and examine how those results relate to the efficacy of these drugs in treating clinical malaria
3 Measure drug levels at 3 days and correlate with efficacy results
4 Examine early clinical parasitologic and clinical predictors of late treatment failure
5 Use the knowledge gained in Aims 1-3 to develop a molecular tool for a countrywide resistance surveillance system for antimalarial drugs
Detailed Description:
Resistance of Plasmodium falciparum to current antimalarial drugs and the continuing development of resistance to new antimalarial formulations is one of the major obstacles to effective malaria control and case management Parasite populations are highly resistant to chloroquine on an almost worldwide basis Central America and Haiti being the exceptions and resistance to the next line of treatment SP is widespread in Asia and large parts of East Africa and South America SP is also now recommended for use as intermittent preventative treatment IPT in pregnancy which adds to concerns about the development and spread of SP resistance More expensive combination drug therapy using artesunate and other antimalarials in combination is increasingly being recommended in an effort to extend the useful life of drugs and to slow the spread of antimalarial drug resistance In all likelihood resistance will eventually emerge for any new single drug or combination formulation that we deploy in the field
Given the above efficient comprehensive and validated methods for monitoring drug resistance in advance of the development of resistance to the antimalarial drugs that are in use are urgently needed Such methods would help malaria control and prevention programs in guiding national treatment recommendations and policies Integrating laboratory expertise analytic methods based on population genetics and more traditional methods of surveillance for anti-malarial drug resistance eg in vivo drug efficacy studies and networking with national and international partners will result in a multidisciplinary geographically diverse team approach to assessing and monitoring drug resistant malaria as well as developing and validating molecular methods This type of effort will greatly assist in maximizing the useful life span of antimalarial drugs and in providing evidence-based guidance for drug policy decisions
Specific Aims
1 Prospectively measure the in vivo response of P falciparum malaria in Mali to CQ SP AQ SPAQ in combination AQartesunate AS in combination SPAS and artemether-lumefantrine Co-artem In one site with preliminary data showing a high rate of P falciparum resistance to MQ MQ will also be tested
2 Measure the frequencies of dihydrofolate reductase dhfr dihydropteroate synthetase dhps P falciparum chloroquine resistance transporter pfcrt and P falciparum multi-drug resistant pfmdr 1 genotypes and establish their relationship with in vivo resistance to SP dhfr and dhps CQ AQ SPAQ AQAS SPAS and MQ
3 Measure drug levels at 3 days and correlate with in vivo efficacy results
4 Examine early clinical parasitologic and clinical predictors of late treatment failure
5 Use the knowledge gained in Aims 1-3 to develop a molecular tool for a countrywide resistance surveillance system for SP AQ and MQ
Study Design
The study will entail two consecutive years of prospective 28 day in vivo drug efficacy studies carried out during the rainy season in three different malaria transmission sites Koro rural town with 71 of resistance to MQ at a lower dose of 15 mgkg Pongono rural town with little exposure to antimalarials and Faladje rural village with 30 of chloroquine resistance Children aged 6-59 months with clinical symptoms consistent with malaria will be enrolled in the study after screening for fever axillary temperature 375 C and malaria asexual parasites identified by microscopic examination of thick blood films
Blood spotted onto filter papers will be collected prior to treatment and during follow up These filter paper samples will be used for the molecular detection of drug resistance-conferring gene polymorphisms as well as the HPLC detection and quantification of the respective drugs and their relevant metabolites In vivo data interpretation will be done using the WHO 28-day protocol WHO 2003 and molecular markers will be used for the determination of the genotype resistance index GRI Venous blood will be collected at enrollment and at the time of in vivo failure to measure in vitro drug efficacy and cryopreserve parasites to search for novel molecular markers to new antimalarial drugs
Given the above efficient comprehensive and validated methods for monitoring drug resistance in advance of the development of resistance to the antimalarial drugs that are in use are urgently needed Such methods would help malaria control and prevention programs in guiding national treatment recommendations and policies Integrating laboratory expertise analytic methods based on population genetics and more traditional methods of surveillance for anti-malarial drug resistance eg in vivo drug efficacy studies and networking with national and international partners will result in a multidisciplinary geographically diverse team approach to assessing and monitoring drug resistant malaria as well as developing and validating molecular methods This type of effort will greatly assist in maximizing the useful life span of antimalarial drugs and in providing evidence-based guidance for drug policy decisions
Specific Aims
1 Prospectively measure the in vivo response of P falciparum malaria in Mali to CQ SP AQ SPAQ in combination AQartesunate AS in combination SPAS and artemether-lumefantrine Co-artem In one site with preliminary data showing a high rate of P falciparum resistance to MQ MQ will also be tested
2 Measure the frequencies of dihydrofolate reductase dhfr dihydropteroate synthetase dhps P falciparum chloroquine resistance transporter pfcrt and P falciparum multi-drug resistant pfmdr 1 genotypes and establish their relationship with in vivo resistance to SP dhfr and dhps CQ AQ SPAQ AQAS SPAS and MQ
3 Measure drug levels at 3 days and correlate with in vivo efficacy results
4 Examine early clinical parasitologic and clinical predictors of late treatment failure
5 Use the knowledge gained in Aims 1-3 to develop a molecular tool for a countrywide resistance surveillance system for SP AQ and MQ
Study Design
The study will entail two consecutive years of prospective 28 day in vivo drug efficacy studies carried out during the rainy season in three different malaria transmission sites Koro rural town with 71 of resistance to MQ at a lower dose of 15 mgkg Pongono rural town with little exposure to antimalarials and Faladje rural village with 30 of chloroquine resistance Children aged 6-59 months with clinical symptoms consistent with malaria will be enrolled in the study after screening for fever axillary temperature 375 C and malaria asexual parasites identified by microscopic examination of thick blood films
Blood spotted onto filter papers will be collected prior to treatment and during follow up These filter paper samples will be used for the molecular detection of drug resistance-conferring gene polymorphisms as well as the HPLC detection and quantification of the respective drugs and their relevant metabolites In vivo data interpretation will be done using the WHO 28-day protocol WHO 2003 and molecular markers will be used for the determination of the genotype resistance index GRI Venous blood will be collected at enrollment and at the time of in vivo failure to measure in vitro drug efficacy and cryopreserve parasites to search for novel molecular markers to new antimalarial drugs
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None